A Study of the Cellular Immune Response to Enteroviruses in Humans: Identification of Cross-reactive T Cell Epitopes on the Structural Proteins of Enteroviruses

Cello, Jerónimo; Strannegård, Örjan; Svennerholm, Bo

doi:10.1099/0022-1317-77-9-2097

Cited by 38 publications

(29 citation statements)

References 45 publications

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“…This phenomenon could be explained by immunological cross-protection induced by CVB3 and CVB6 against the diabetogenic effect of CVB1. Such cross-protection, most likely due to cell-mediated immunity, has been reported in other virus diseases, such as among different rotavirus, papillomavirus, and poliovirus types (33)(34)(35)(36)(37). Crossprotection is also supported by the increased CVB1-related risk in children who were infected by CVB1 but none of the protective serotypes.…”

Section: Discussionsupporting

confidence: 48%

Coxsackievirus B1 Is Associated With Induction of β-Cell Autoimmunity That Portends Type 1 Diabetes

Laitinen¹,

Honkanen

Pakkanen³

et al. 2014

Diabetes

227

221

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The rapidly increasing incidence of type 1 diabetes implies that environmental factors are involved in the pathogenesis. Enteroviruses are among the suspected environmental triggers of the disease, and the interest in exploring the possibilities to develop vaccines against these viruses has increased. Our objective was to identify enterovirus serotypes that could be involved in the initiation of the disease process by screening neutralizing antibodies against 41 different enterovirus types in a unique longitudinal sample series from a large prospective birth-cohort study. The study participants comprised 183 case children testing persistently positive for at least two diabetes-predictive autoantibodies and 366 autoantibody-negative matched control children. Coxsackievirus B1 was associated with an increased risk of β-cell autoimmunity. This risk was strongest when infection occurred a few months before autoantibodies appeared and was attenuated by the presence of maternal antibodies against the virus. Two other coxsackieviruses, B3 and B6, were associated with a reduced risk, with an interaction pattern, suggesting immunological cross-protection against coxsackievirus B1. These results support previous observations suggesting that the group B coxsackieviruses are associated with the risk of type 1 diabetes. The clustering of the risk and protective viruses to this narrow phylogenetic lineage supports the biological plausibility of this phenomenon.

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Section: Discussionsupporting

confidence: 48%

Coxsackievirus B1 Is Associated With Induction of β-Cell Autoimmunity That Portends Type 1 Diabetes

Laitinen¹,

Honkanen

Pakkanen³

et al. 2014

Diabetes

227

221

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show abstract

“…It is possible but not proved by the data available that this maternal infection also spread to the fetus. As T-cell responses to enteroviruses are known to include reactions to cross-reactive epitopes in capsid protein [7], the putative fetal echovirus 6 infection might be responsible for the reactivity we observed to coxsackievirus B4 antigens. The Tcell response was clearly positive 3 months but no longer at 12 months after birth, supporting the diagnosis of an intrauterine infection.…”

Section: Discussionmentioning

confidence: 64%

“…The results are expressed as stimulation indexes (SI). As an enterovirus antigen we used only CBV-4 because it has been shown that human T-cell epitopes are cross-reactive among different enteroviruses [7].…”

Section: Methodsmentioning

confidence: 99%

Neonatal Type I diabetes associated with maternal echovirus 6 infection: a case report

et al. 2000

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“…Children with CBV infection had stronger T-cell responses to CBV4 antigen when compared to either children with other enterovirus infections or children without any serological evidence of enterovirus infection. These data demonstrated the specificity of our assay to CBVs despite the large cellular cross-reactivity between enteroviruses, which also contributes to the responsiveness (22,23).…”

Section: Discussionmentioning

confidence: 92%

“…In addition to CBV4, a stronger response was also observed to purified PV1; all our children had a history of several doses of inactivated Salk polio vaccination. The strong cross-reactivity of T-cell responses to different enterovirus serotypes (22,23) suggests that the stronger response to purified PV antigen may be associated with an increased number of various enterovirus infections in diabetic children.…”

Section: Discussionmentioning

confidence: 99%

T-cell responses to enterovirus antigens in children with type 1 diabetes.

et al. 2000

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Enterovirus infections, implicated in the pathogenesis of type 1 diabetes in a number of studies, may precipitate the symptoms of clinical diabetes and play a role in the initiation of the ␤-cell damaging process. The aim of this study was to evaluate whether cellular immune responses to enterovirus antigens are abnormal in children with type 1 diabetes. Lymphocyte proliferation responses to enterovirus antigens were analyzed in 41 children with new-onset type 1 diabetes, 23 children with type 1 diabetes for 4-72 months, and healthy control children in subgroups matched for HLA-DQB1 risk alleles, sex, and age. Children with diabetes for 4-72 months more often had T-cell responses to the Coxsackievirus B4-infected cell lysate antigen than children with new-onset diabetes (P < 0.01) or control children (P < 0.01). Responses to recombinant nonstructural protein 2C of Coxsackievirus B4 were also more frequent in children with type 1 diabetes for 4-72 months when compared with control subjects (P = 0.03), whereas the responses to purified Coxsackievirus B4 and recombinant VP0 protein, which did not contain nonstructural proteins, did not differ. These data suggest that T-cell responses to Coxsackievirus B4 proteins and particularly to the antigens containing the nonstructural proteins of the virus are increased in children with type 1 diabetes after the onset of the disease. However, in children with new-onset diabetes, responses were normal or even decreased. This phenomenon was specific for enteroviruses and could be caused by trapping of enterovirus-specific T-cells in the pancreas.

show abstract

A Study of the Cellular Immune Response to Enteroviruses in Humans: Identification of Cross-reactive T Cell Epitopes on the Structural Proteins of Enteroviruses

Cited by 38 publications

References 45 publications

Coxsackievirus B1 Is Associated With Induction of β-Cell Autoimmunity That Portends Type 1 Diabetes

Coxsackievirus B1 Is Associated With Induction of β-Cell Autoimmunity That Portends Type 1 Diabetes

Neonatal Type I diabetes associated with maternal echovirus 6 infection: a case report

T-cell responses to enterovirus antigens in children with type 1 diabetes.

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